Combination Therapy Approved for Melanoma Mutation

This morning, it was announced by Novartis that the U.S. Food and Drug Administration (FDA) has approved dabrafenib (Tafinlar) in combination with trametinib (Mekinist) for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutation, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection.

In December 2017, the combination was granted Priority Review, and 2 months earlier in October, it was granted Breakthrough Therapy designation. Its original approval was for patients with unresectable or metastatic melanoma with a BRAF V600E/K mutation as detected by an FDA-approved test and non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, which came in November 2015.

Tafinlar is a BRAF inhibitor, while Mekinist is an MEK 1/2 inhibitor, and approval of the combination is based primary endpoints that were met in the COMBI-AD phase 3 study, which enrolled 870 patients with stage 3 BRA V600E/K mutation-positive melanoma who had undergone complete resection. Tafinlar + Mekinist reduced the risk of disease recurrence or death by 53% in comparison to placebo.

"Since the initial approval of Tafinlar and Mekinist in metastatic melanoma in 2013, the combination has become an important therapy for many patients carrying a BRAF mutation in both melanoma and lung cancers," said Liz Barrett, CEO, Novartis Oncology in a press release. "Today's FDA approval is an important milestone for patients who previously had limited treatment options in the adjuvant setting, and reflects our commitment to the ongoing development of this breakthrough treatment."

Key secondary endpoints were also met in the COMBI-AD study, and the combination treatment group also demonstrated improvement in overall survival (OS), remaining consistent with the efficacy profile of the therapy, which have shown its ability to significantly improve OS when compared to monotherapies.

Improvements were also observed in distant metastasis-free survival (DMFS) and freedom from relapse (FFR).

"Prevention and early detection are important safeguards from melanoma, but that's only half the picture. Melanoma is an aggressive cancer that can recur, particularly when it shows certain warning signs like increased depth, ulceration, or spread to the lymph nodes," said Sancy Leachman, M.D., Ph.D., Chair of the Department of Dermatology at OHSU School of Medicine.

"With proven treatment options for these patients, it is important for dermatologists to assure that appropriate patients are offered adjuvant treatment options — a 'watch and wait' approach is no longer the standard of care. Collaborating with a multidisciplinary care team of surgeons, pathologists and oncologists, and determining the right treatment based on the patient's individual circumstances and mutational status is crucial to our patients' care plans."

Adverse events (AEs) throughout the phase 3 were consistent with other historical studies of Tafinlar + Mekinist, and no new safety signals were reported. Of patients treated with the combination, 97% experienced an AE, 41% had grade 3/4 AEs and 26% had AEs leading to treatment discontinuation (vs. 88%, 14%, and 3%, respectively, with placebo).

Full results from the COMBI-AD study were published in the New England Journal of Medicine in October 2017.

For more from the FDA, follow Rare Disease Report on Facebook and Twitter.

References:

1. Novartis receives FDA approval of Tafinlar® + Mekinist® for adjuvant treatment of BRAF V600-mutant melanoma. https://www.prnewswire.com/news-releases/novartis-receives-fda-approval-of-tafinlar--mekinist-for-adjuvant-treatment-of-braf-v600-mutant-melanoma-300639403.html. Accessed May 1, 2018.
2. Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib Plus Trametinib for Stage III BRAF V600E/K—Mutant Melanoma. New England Journal of Medicine. 2017; 377:1813-18 DOI: 10.1056/NEJMoa1708539.